EP1814859A2 - Procedes de preparation de composes indazole - Google Patents

Procedes de preparation de composes indazole

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Publication number
EP1814859A2
EP1814859A2 EP05797459A EP05797459A EP1814859A2 EP 1814859 A2 EP1814859 A2 EP 1814859A2 EP 05797459 A EP05797459 A EP 05797459A EP 05797459 A EP05797459 A EP 05797459A EP 1814859 A2 EP1814859 A2 EP 1814859A2
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EP
European Patent Office
Prior art keywords
formula
compound
alkyl
aryl
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05797459A
Other languages
German (de)
English (en)
Inventor
Srinivasan Agouron Pharmaceuticals Inc. BABU
Raymond Jr. Agouron Pharmaceuticals Inc. DAGNINO
Aubrey Agouron Pharmaceuticals Inc. HADDACH
Mark Bryan Agouron Pharmaceuticals Inc. MITCHELL
Michael A. Agouron Pharmaceuticals Inc. OUELLETTE
James E. Pfizer Global Research and Dev. SAENZ
Jayaram K. Agouron Pharmaceuticals Inc. SRIRANGAM
Shu Agouron Pharmaceuticals Inc. YU
Scott Edward Agouron Pharmaceuticals Inc. ZOOK
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Pfizer Inc
Original Assignee
Pfizer Inc
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Filing date
Publication date
Application filed by Pfizer Inc filed Critical Pfizer Inc
Publication of EP1814859A2 publication Critical patent/EP1814859A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to methods for preparing indazole compounds, and intermediates thereof, which are useful as modulators and/or inhibitors of protein kinases.
  • U.S. Patent Nos. 6,531 ,491 and 6,534,524 which are incorporated herein by reference in their entirety, are directed to indazole compounds that modulate and/or inhibit the activity of certain protein kinases such as VEGF-R (vascular endothelial cell growth factor receptor), FGF-R (fibroblast growth factor receptor), CDK (cyclin-dependent kinase) complexes, CHK1 , LCK (also known as lymphocyte-specific tyrosine kinase), TEK (also known as Tie-2), FAK (focal adhesion kinase), and/or phosphorylase kinase.
  • VEGF-R vascular endothelial cell growth factor receptor
  • FGF-R fibroblast growth factor receptor
  • CDK cyclin-dependent kinase complexes
  • CHK1 vascular endothelial cell growth factor receptor
  • LCK also known as lymphocyte-specific tyrosine kinase
  • R 8 is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, or aryloxyl;
  • R 10 is independently selected from hydrogen, halogen, and lower-alkyl; and pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and pharmaceutically acceptable salts thereof.
  • R 2 is (C 1 to C 12 ) alkyl, (C 2 to C 12 ) alkenyl, (C 3 to C 12 ) cycloalkyl, (5 to 12-membered) heterocycloalkyl, (C 6 to C 12 ) aryl, (5 to 12-membered) heteroaryl, (C 1 to C 12 ) alkoxy, (C 6 to
  • each R 3 is independently hydrogen, halogen, or (C 1 to C 8 ) alkyl, and the (C 1 to C 8 ) alkyl is substituted with 0 to 4 R 5 groups;
  • R 4 is (C 1 to C 12 ) alkyl, (C 3 to C 12 ) cycloalkyl, (5 to 12-membered) heterocycloalkyl, (C 6 to C 12 ) aryl, or (5 to 12-membered) heteroaryl, and R 4 is substituted with 0 to 4 R 5 groups; each R 5 is independently halogen, (C 1 to C 8 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl,
  • the reaction occurs in the presence of a catalyst and a base; W is a protecting group; X is an activated substituent group; R 1 , R 2 , R 3 , R 4 , and R 5 are as described above; and b) deprotecting the compound of formula IV to provide the compound of formula I.
  • the invention relates to methods for preparing a compound of formula I, wherein the catalyst is a palladium catalyst.
  • the invention relates to methods for preparing a compound of formula I, wherein the catalyst is Pd 2 (dba) 3 and the reaction further comprises a ligand that complexes with the Pd 2 (dba) 3 catalyst.
  • the invention relates to methods for preparing a compound of formula I, wherein the ligand is a phosphene ligand.
  • the invention relates to methods for preparing a compound of formula I, wherein the ligand is 2-(di-f-butylphosphino)biphenyl.
  • the invention relates to methods for preparing a compound of formula I, wherein the base is potassium carbonate, sodium carbonate, cesium carbonate, sodium f-butoxide, potassium f-butoxide, triethylamine, or mixtures thereof.
  • the invention relates to methods for preparing a compound of formula I, wherein the base is sodium f-butoxide.
  • the invention relates to methods for preparing a compound of formula I, further comprising a solvent in the reaction between the compound of formula Il and the compound of formula III. In another aspect, the invention relates to methods for preparing a compound of formula I, further comprising a solvent.
  • the invention relates to methods for preparing a compound of formula I, wherein the reaction is carried out at about 100 0 C.
  • the invention relates to methods for preparing a compound of formula I, wherein W is a tetrahydropyran protecting group or is a trimethylsilylethoxymethyl protecting group.
  • the invention relates to methods for preparing a compound of formula I, wherein the activated substituent group X is chloride, bromide, or iodide.
  • the invention relates to methods for preparing a compound of formula I, wherein the activated substituent group X is bromide.
  • the invention relates to methods for preparing a compound of formula I, wherein W is a tetrahydropyran protecting group and the process of deprotecting comprises reacting the compound of formula IV with an acid in an alcoholic solvent.
  • the invention relates to methods for preparing a compound of formula I, wherein the acid is methanesulfonic acid, and the alcoholic solvent is methanol, ethanol, n-propanol or isopropanol.
  • the invention relates to methods for preparing a compound of formula I, wherein the compound of formula Il has formula V, and the compound of formula III has formula Vl:
  • the invention relates to methods for preparing a compound of formula I, wherein the compound of formula IV has formula VII: -A-
  • the invention relates to methods for preparing a compound of formula I, wherein the compound of formula I has formula VIII:
  • the invention relates to methods for preparing a compound of formula II:
  • R 4 is (C-] to Ci 2 ) alkyl, (C 3 to C 12 ) cycloalkyl, (5 to 12-membered) heterocycloalkyl, (C 6 to C 12 ) aryl, or (5 to 12-membered) heteroaryl, and R 4 is substituted with 0 to 4 R 5 groups; each R 5 is independently halogen, (Ci to C 8 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl,
  • W is a protecting group; comprising: a) protecting 6-nitro indazole with a nitrogen protecting group W; b) functionalizing the C-3 position of the indazole ring with an R 1 group; and c) reducing the 6-nitro group to a 6-amino group.
  • the invention relates to methods for preparing a compound of formula II, wherein the protecting group W is a tetrahydropyran protecting group or is a trimethylsilylethoxymethyl protecting group.
  • the invention relates to methods for preparing a compound of formula II, wherein the C-3 position of the indazole ring is functionalized by: a) iodination with a metal halide to provide a N-1 protected (W) 3-iodo-6-nitro- indazole compound, and b) coupling the N-1 protected (W) 3-iodo-6-nitro-indazole compound with R 1 by a palladium catalyzed reaction.
  • the invention relates to methods for preparing a compound of formula II, wherein the metal halide is potassium iodide, and the palladium catalyzed reaction is a Heck reaction.
  • the invention relates to methods for preparing a compound of formula II, wherein R 1 is 2-vinyl pyridine.
  • the invention relates to methods for preparing a compound of formula II, wherein the compound of formula Il has formula IX:
  • W is a tetrahydropyran protecting group or is a trimethylsilylethoxymethyl protecting group.
  • the invention relates to methods for preparing a compound of formula II, wherein the compound of formula Il has formula X:
  • the invention relates to methods for preparing a compound of formula III:
  • R 2 is (Ci to C 12 ) alkyl, (C 2 to C 12 ) alkenyl, (C 3 to C 12 ) cycloalkyl, (5 to 12-membered) heterocycloalkyl, (C 6 to C 12 ) aryl, (5 to 12-membered) heteroaryl, (C 1 to C 12 ) alkoxy, (C 6 to C 12 ) aryloxy, and R 2 is substituted with 0 to 4 R 5 groups; each R 3 is independently hydrogen, halogen, or (C 1 to C 8 ) alkyl, and the (C 1 to C 8 ) alkyl is substituted with 0 to 4 R 5 groups; each R 5 is independently halogen, (C 1 to C 8 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl,
  • X is an activated substituent group; comprising, reacting a compound of formula Xl with a compound of formula XII:
  • the invention relates to methods for preparing a compound of formula III, wherein the leaving group Y is chloride.
  • the invention relates to methods for preparing a compound of formula III, wherein the compound of formula Xl has formula XIII, the compound of formula XII has formula XIV, and the compound of formula III has formula XV:
  • the invention relates to methods for preparing a compound of formula III:
  • R 2 is (C- I to C 12 ) alkyl, (C 2 to C 12 ) alkenyl, (C 3 to C 12 ) cycloalkyl, (5 to 12-membered) heterocycloalkyl, (C 6 to C 12 ) aryl, (5 to 12-membered) heteroaryl, (C 1 to C 12 ) alkoxy, (C 6 to C- I2 ) aryloxy, and R 2 is substituted with O to 4 R 5 groups; each R 3 is independently hydrogen, halogen, or (C 1 to C 8 ) alkyl, and the (C 1 to C 8 ) alkyl is substituted with O to 4 R 5 groups; each R 5 is independently halogen, (C 1 to C 8 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, -OH, -NO 2 , -CN, -CO 2 H, -0(C 1 to C 8 alkyl), (C 6
  • X is an activated substituent group.
  • the invention relates to methods for preparing a compound of formula III, wherein the compound of formula III has formula XV:
  • X is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
  • substituents it is meant to indicate that the group in question may optionally be substituted by one or more of the substituents provided.
  • the number of substituents a group in the compounds of the invention may have depends on the number of positions available for substitution.
  • An aryl ring in the compounds of the invention may contain from 1 to 5 additional substituents, depending on the degree of substitution present on the ring. The maximum number of substituents that a group in the compounds of the invention may have can be easily determined.
  • react refers to a chemical process or processes in which two or more reactants are allowed to come into contact with each other to effect a chemical change or transformation.
  • reactant A and reactant B are allowed to come into contact with each other to afford a new chemical compound(s) C, A is said to have "reacted” with B to produce C.
  • protecting refers to a process in which a functional group in a chemical compound is selectively masked by a non-reactive functional group in order to allow a selective reaction(s) to occur elsewhere on said chemical compound.
  • non-reactive functional groups are herein termed "protecting groups.”
  • nitrogen protecting group refers to those groups that are capable of selectively masking the reactivity of a nitrogen (N) group.
  • suitable protecting group refers to those protecting groups that are useful in the preparation of the compounds of the present invention. Such groups are generally able to be selectively introduced and removed using mild reaction conditions that do not interfere with other portions of the subject compounds.
  • Protecting groups that are suitable for use in the processes and methods of the present invention are well known. The chemical properties of such protecting groups, methods for their introduction and their removal can be found in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3 rd ed.), John Wiley & Sons, NY (1999), herein incorporated by reference in its entirety.
  • the terms "deprotect,” “deprotected,” and “deprotecting,” as used herein, are meant to refer to the process of removing a protecting group from a compound.
  • leaving group refers to a chemical functional group that generally allows a nucleophilic substitution reaction to take place at the atom to which it is attached.
  • the -Cl group is generally referred to as a leaving group because it allows nucleophilic substitution reactions to take place at the carbonyl carbon.
  • Suitable leaving groups are well known, for example, halides, aromatic heterocycles, cyano, amino groups (generally under acidic conditions), ammonium groups, alkoxide groups, carbonate groups, formates, and hydroxy groups that have been activated by reaction with compounds such as carbodiimides.
  • Suitable leaving groups include, but are not limited to, chloride, bromide, iodide, cyano, imidazole, and hydroxy groups that have been allowed to react with a carbodiimide such as dicyclohexylcarbodiimide (optionally in the presence of an additive such as hydroxybenzotriazole) or a carbodiimide derivative.
  • activated substituent group refers to a chemical functional group that generally allows a substitution reaction to take place at the atom to which it is attached. In aryl iodides, the -I group is generally referred to as an activated substituent group because it allows substitution reactions to take place at the aryl carbon.
  • Suitable activated substituent groups are well known and can include halides (chloride, bromide, iodide), activated hydroxyl groups (e.g., triflate, mesylate, and tosylate), and diazonium salts.
  • alkyl represents a straight- or branched-chain saturated hydrocarbon, containing 1 to 10 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described below.
  • exemplary alkyl substituents include, but are not limited to methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-butyl, and the like.
  • alkenyl represents a straight- or branched-chain hydrocarbon, containing one or more carbon-carbon double bonds and having 2 to 10 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described below.
  • alkenyl substituents include, but are not limited to ethenyl, propenyl, butenyl, allyl, pentenyl and the like.
  • phenyl refers to a fully unsaturated 6-membered carbocyclic group.
  • a "phenyl” group may also be referred to herein as a benzene derivative.
  • heteroaryl refers to a group comprising an aromatic monovalent monocyclic, bicyclic, or tricyclic group, containing 5 to 18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents described below.
  • heteroaryl is also intended to encompass the N-oxide derivative (or N-oxide derivatives, if the heteroaryl group contains more than one nitrogen such that more than one N-oxide derivative may be formed) of the nitrogen-containing heteroaryl groups described herein.
  • heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, te
  • N-oxide derivatives of heteroaryl groups include, but are not limited to, pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, triazinyl N-oxide, isoquinolyl N-oxide, and quinolyl N-oxide.
  • heteroaryl groups include the following moieties:
  • halide represents fluoro, chloro, bromo or iodo substituents.
  • polymorph refers to a crystalline form of a compound with a distinct spatial lattice arrangement as compared to other crystalline forms of the same compound.
  • amorphous refers to a non-crystalline form of a compound.
  • a pharmaceutically acceptable salt is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable.
  • a compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenz
  • an inventive compound or an intermediate in the present invention is a base
  • a desired salt may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such
  • a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • the compounds of the present invention may contain at least one chiral center and may exist as single stereoisomers (e.g., single enantiomers or single diastereomers), any mixture of stereoisomers (e.g., any mixture of enantiomers or diastereomers) or racemic mixtures thereof. It is specifically contemplated that, unless otherwise indicated, all stereoisomers, mixtures and racemates of the present compounds are encompassed within the scope of the present invention. Compounds identified herein as single .stereoisomers are meant to describe compounds that are present in a form that contains at least from at least about 90% to at least about 99% of a single stereoisomer of each chiral center present in the compounds.
  • stereochemistry of the chiral carbons present in the chemical structures illustrated herein are not specified, it is specifically contemplated that all possible stereoisomers are encompassed therein.
  • the compounds of the present invention may be prepared and used in stereoisomerically pure form or substantially stereoisomerically pure form.
  • stereoisomeric purity refers to the "enantiomeric” purity and/or “diastereomeric” purity of a compound.
  • stereoisomerically pure form is meant to encompass those compounds that contain from at least about 95% to at least about 99%, and all values in between, of a single stereoisomer.
  • substantially enantiomerically pure as used herein is meant to encompass those compounds that contain from at least about 90% to at least about 95%, and all values in between, of a single stereoisomer.
  • diastereomerically pure is meant to encompass those compounds that contain from at least about 95% to at least about 99%, and all values in between, of a single diastereoisomer.
  • substantially diastereomerically pure is meant to encompass those compounds that contain from at least about 90% to at least about 95%, and all values in between, of a single diastereoisomer.
  • racemic or “racemic mixture,” as used herein, refer to a mixture containing equal amounts of stereoisomeric compounds of opposite configuration.
  • a racemic mixture of a compound containing one stereoisomeric center would comprise equal amount of that compound in which the stereoisomeric center is of the (S)- and ⁇ -configurations.
  • enantiomerically enriched is meant to refer to those compositions wherein one stereoisomer of a compound is present in a greater amount than the opposite stereoisomer.
  • diastereomerically enriched refers to those compositions wherein one diastereomer of compound is present in amount greater than the opposite diastereomer.
  • the compounds of the present invention may be obtained in stereoisomerically pure (i.e., enantiomerically and/or diastereomerically pure) or substantially stereoisomerically pure (i.e., substantially enantiomerically and/or diastereomerically pure) form. Such compounds may be obtained synthetically, according to the procedures described herein using stereoisomerically pure or substantially stereoisomerically pure materials.
  • these compounds may be obtained by resolution/separation of mixtures of stereoisomers, including racemic and diastereomeric mixtures, using well known procedures.
  • Exemplary methods that may be useful for the resolution/separation of stereoisomeric mixtures include derivitation with stereochemical ⁇ pure reagents to form diastereomeric mixtures, chromatographic separation of diastereomeric mixtures, chromatographic separation of enantiomeric mixtures using chiral stationary phases, enzymatic resolution of covalent derivatives, and crystallization/re-crystallization.
  • Other useful methods may be found in Enantiomers. Racemates. and Resolutions. J. Jacques, et al., 1981, John Wiley and Sons, New York, NY, the disclosure of which is incorporated herein by reference.
  • Preferred stereoisomers of the compounds of this invention are described herein.
  • FIG. 1 A is an X-ray powder diffraction diagram of polymorph Form I of the invention
  • FIG. 1 B is a Differential Scanning Calorimetry (DSC) thermogram of polymorph Form I of the invention
  • FIG. 1C is a Raman spectral diagram of polymorph Form I of the invention
  • FIG. 2A is an X-ray powder diffraction diagram of polymorph Form Il of the invention
  • FIG. 2B is a DSC thermogram of polymorph Form Il of the invention
  • FIG. 2C is a Raman spectral diagram of polymorph Form Il of the invention
  • FIG. 3A is an X-ray powder diffraction diagram of polymorph Form III of the invention
  • FIG. 3B is a DSC thermogram of polymorph Form III of the invention
  • FIG. 3C is a Raman spectral diagram of polymorph Form III of the invention
  • FIG. 4A is an X-ray powder diffraction diagram of polymorph Form IV of the invention
  • FIG. 4B is a DSC thermogram of polymorph Form IV of the invention
  • FIG. 4C is a Raman spectral diagram of polymorph Form IV of the invention
  • FIG. 5A is an X-ray powder diffraction diagram of polymorph Form V of the invention
  • FIG. 5B is a DSC thermogram of polymorph Form V of the invention
  • FIG. 5C is a Raman spectral diagram of polymorph Form V of the invention
  • FIG. 6A is an X-ray powder diffraction diagram of polymorph Form Ia of the invention
  • FIG. 6B is a DSC thermogram of polymorph Form Ia of the invention
  • FIG. 7A is an X-ray powder diffraction diagram of polymorph Form Ib of the invention
  • FIG. 7B is a DSC thermogram of polymorph Form Ib of the invention
  • FIG. 7C is a Raman spectral diagram of polymorph Form Ib of the invention
  • FIG. 8A is an X-ray powder diffraction diagram of polymorph Form Ha of the invention
  • FIG. 8B is a DSC thermogram of polymorph Form Na of the invention
  • FIG. 9A is an X-ray powder diffraction diagram of polymorph Form Mb of the invention
  • FIG. 9B is a DSC thermogram of polymorph Form Hb of the invention
  • FIG. 9C is a Raman spectral diagram of polymorph Form Hb of the invention
  • FIG. 10A is an X-ray powder diffraction diagram of polymorph Form IHa of the invention
  • FIG. 11A is an X-ray powder diffraction diagram of polymorph Form lllb of the invention
  • FIG. 11 B is a DSC thermogram of polymorph Form HIb of the invention
  • FIG. 11C is a Raman spectral diagram of polymorph Form IHb of the invention
  • FIG. 12A is an X-ray powder diffraction diagram of polymorph Form IVa of the invention
  • FIG. 12B is a DSC thermogram of polymorph Form IVa of the invention
  • FIG. 13A is an X-ray powder diffraction diagram of polymorph Form Va of the invention
  • FIG. 13B is a DSC thermogram of polymorph Form Va of the invention
  • FIG. 13C is a Raman spectral diagram of polymorph Form Va of the invention
  • FIG. 14A is an X-ray powder diffraction diagram of polymorph Form Vl of the invention
  • FIG. 14B is a DSC thermogram of polymorph Form Vl of the invention
  • FIG. 14C is a Raman spectral diagram of polymorph Form Vl of the invention
  • FIG. 15A is an X-ray powder diffraction diagram of an amorphous form of the invention
  • FIG. 15B is a Raman spectral diagram of an amorphous form of the invention.
  • FIG 16 is an X-ray powder diffraction diagram of polymorph Form lbm-2 of the invention
  • the indazole compounds of formula I can be prepared from 6-nitroindazole.
  • the indazole ring can be substituted at the C-3 position with an R 1 group as described herein, using known reagents and reactions.
  • the C-3 position of the indazole ring can be functionalized by reacting 6-nitroindazole with iodine (I 2 ) in the presence of a base such as potassium carbonate (K 2 CO 3 ), and in a solvent such as DMF, to provide 3-iodo-6-nitro- indazole.
  • a base such as potassium carbonate (K 2 CO 3 )
  • DMF solvent
  • the C-3 position of the indazole ring can then be elaborated to a desired R 1 group using known reactions, such as a Suzuki reaction or a Heck reaction.
  • the intermediates useful for the preparation of the compounds of formula I may require the use of protecting groups.
  • the indazole ring nitrogen (N-1) may require masking through use of a suitable protecting group.
  • the substituents on these intermediates are themselves not compatible with the synthetic methods of this invention, the substituents may be protected with suitable protecting groups that are stable to the reaction conditions used in these methods.
  • the protecting groups may be removed at a suitable point in the reaction sequence of the method to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known, examples of which may be found in T. Greene and P. Wuts, supra.
  • a suitable nitrogen protecting group, W is one that is stable to the reaction conditions in which the compounds of formula Il are allowed to react with the compounds of formula III to provide the compounds of formula IV. Furthermore, such a protecting group should be chosen so that it can be subsequently removed to provide the compounds of formula I.
  • nitrogen protecting groups are well known and any nitrogen protecting group that is useful in the methods of preparing the compounds of this invention or may be useful in the protein kinase inhibitory compounds of this invention may be used.
  • Exemplary nitrogen protecting groups include silyl, substituted silyl, alkyl ether, substituted alkyl ether, cycloalkyl ether, substituted cycloalkyl ether, alkyl, substituted alkyl, carbamate, urea, amide, imide, enamine, sulfenyl, sulfonyl, nitro, nitroso, oxide, phosphinyl, phosphoryl, silyl, organometallic, borinic acid and boronic acid groups.
  • suitable nitrogen protecting groups useful as W include, but are not limited to, silyl protecting groups (e.g., SEM: trimethylsilylethoxymethyl, TBDMS: f-butyldimethylsilyl); alkyl ether protecting groups such as cycloalkyl ethers (e.g., THP: tetrahydropyran); carbamate protecting groups such as alkyloxycarbonyl (e.g., Boc: t-butyloxycarbonyl), aryloxycarbonyl (e.g., Cbz: benzyloxycarbonyl, and FMOC: fluorene-9-methyloxycarbonyl), alkyloxycarbonyl (e.g., methyloxycarbonyl), alkylcarbonyl or arylcarbonyl, substituted alkyl, especially
  • W is a silyl protecting group (e.g., SEM: trimethylsilylethoxymethyl, TBDMS: t- butyldimethylsilyl), such groups may be applied and subsequently removed under known conditions.
  • silyl protecting groups may be attached to nitrogen and moieties and hydroxyl groups via their silyl chlorides (e.g., SEMCI: trimethylsilylethoxymethyl chloride, TBDMSCI: f-butyldimethylsilyl chloride) in the presence of a suitable base (e.g., potassium carbonate), catalyst (e.g., 4-dimethylaminopyridine (DMAP)), and solvent (e.g, DMF or N 1 N- dimethylformamide).
  • a suitable base e.g., potassium carbonate
  • catalyst e.g., 4-dimethylaminopyridine (DMAP)
  • solvent e.g, DMF or N 1 N- dimethylformamide
  • Such silyl protecting groups may be cleaved by exposure of the subject compound to a source of fluoride ions, such as the use of an organic fluoride salt such as a tetraalkylammonium fluoride salt, or an inorganic fluoride salt.
  • Suitable fluoride ion sources include, but are not limited to, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrapropylammonium fluoride, tetrabutylammonium fluoride, sodium fluoride, and potassium fluoride.
  • silane protecting groups may be cleaved under acidic conditions using organic or mineral acids, with or without the use of a buffering agent.
  • Suitable acids include, but are not limited to, hydrofluoric acid, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citric acid, and methanesulfonic acid.
  • Such silane protecting groups may also be cleaved using appropriate Lewis acids.
  • Suitable Lewis acids include, but are not limited to, dimethylbromo borane, triphenylmethyl tetrafluoroborate, and certain Pd (II) salts.
  • Such silane protecting groups can also be cleaved under basic conditions that employ appropriate organic or inorganic basic compounds.
  • Such basic compounds include, but are not limited to, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide.
  • the cleavage of a silane protecting group may be conducted in an appropriate solvent that is compatible with the specific reaction conditions chosen and will not interfere with the desired transformation.
  • suitable solvents include alkyl esters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers, alkylaryl esters, cyclic ethers, hydrocarbons, alcohols, halogenated solvents, alkyl nitriles, aryl nitriles, alkyl ketones, aryl ketones, alkylaryl ketones, or non-protic heterocyclic compounds.
  • Suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, N 1 N- dimethyl formamide, dimethyl acetamide, propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 , 4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1- propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloroform,
  • W is a cyclic ether protecting group (e.g., a tetrahydropyran (THP) group)
  • THP tetrahydropyran
  • Such cyclic ethers may be attached to nitrogen moieties and hydroxyl groups via their enol ethers (e.g., dihydropyran (DHP)) in the presence of a suitable acid (e.g., para-toluenesulfonic acid or methanesulfonic acid), and solvent (e.g., methylene chloride).
  • DHP dihydropyran
  • Such cyclic ether groups may be cleaved by treating the subject compound with organic or inorganic acids or Lewis acids.
  • a particular reagent will depend upon the type of ether present as well as the other reaction conditions.
  • the choice of a suitable reagent for cleaving such a cyclic ether are well known.
  • suitable reagents include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, para-toluenesulfonic acid, methanesulfonic acid, or Lewis acids such as boron trifluoride etherate.
  • solvents that are compatible with the specific reaction conditions chosen and will not interfere with the desired transformation.
  • suitable solvents include alkyl esters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers, alkylaryl esters, cyclic ethers, hydrocarbons, alcohols, halogenated solvents, alkyl nitriles, aryl nitriles, alkyl ketones, aryl ketones, alkylaryl ketones, or non-protic heterocyclic compounds.
  • Suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, N,N-dimethyl formamide, dimethyl acetamide, propionitrile, butyronitrile, t- amyl alcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloro
  • N-1 indazole ring nitrogen Protection of the N-1 indazole ring nitrogen is accomplished by reacting 3-iodo-6- nitroindazole with 3,4-dihydro-2H-pyran and methanesulfonic acid in a solvent, such as DMF, tetrahydrofuran (THF), and methylene chloride (CH 2 CI 2 ) to provide 3-iodo-6-nitro-1- (tetrahydropyran-2-yl)-1 H-indazole.
  • a solvent such as DMF, tetrahydrofuran (THF), and methylene chloride (CH 2 CI 2 )
  • Suitable hydroxyl protecting groups that are useful in the present invention include, but are not limited to, alkyl or aryl esters, alkyl silanes, aryl silanes or alkylaryl silanes, alkyl or aryl carbonates, benzyl groups, substituted benzyl groups, ethers, or substituted ethers.
  • the various hydroxyl protecting groups can be applied and suitably cleaved utilizing a number of known reaction conditions. The particular conditions used will depend on the particular protecting group as well as the other functional groups contained in the subject compound. Furthermore, suitable conditions include the use of an appropriate solvent that is compatible with the reaction conditions utilized and will not interfere with the desired transformation.
  • Suitable solvents useful in applying the various protecting groups and their subsequent removal may include alkyl esters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers, alkylaryl esters, cyclic ethers, hydrocarbons, alcohols, halogenated solvents, alkyl nitriles, aryl nitriles, alkyl ketones, aryl ketones, alkylaryl ketones, and non-protic heterocyclic compounds.
  • Suitable solvents include, but are not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene, N,N-dimethyl formamide, dimethyl acetamide, propionitrile, butyronitrile, t- amyl alcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenyl ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane, chloro
  • the C-3 position of the indazole ring can be elaborated to a desired R 1 group through a Suzuki or Heck reaction, using the appropriate catalyst, ligand, aryl, heteroaryl and/or olefinic species.
  • the Suzuki reaction is a palladium catalyzed coupling reaction in which the reaction of an optionally substituted aryl boronic acid or an optionally substituted heteroaryl boronic acid is coupled with a substituted aryl group or a substituted heteroaryl group, in which the substituents on the aryl group or the heteroaryl group are halide, triflate, or a diazonium salt, which produces a di-aryl species.
  • Useful palladium catalysts for the Suzuki reaction includes but are not limited to Pd(C 17 H 14 O) x , Pd(PPh 3 ) 4, and [Pd(OAc) 2 ] 3, and the like.
  • a base such as an inorganic base or an organic base (e.g., organic amine) is also required to neutralize the liberated acid.
  • Suzuki coupling reactions require milder conditions than Heck reactions.
  • R 1 is a substituted or unsubstituted aryl group, or is a substituted or unsubstituted heteroaryl group
  • the compounds of formula I can be prepared by a Suzuki reaction between an optionally substituted aryl or heteroaryl boronic acid and a substituted aryl or heteroaryl group, in which the substituents on the aryl or heteroaryl group are halide, triflate, or a diazonium salt.
  • a Heck reaction involves the catalytic coupling of C-C bonds, where a vinylic hydrogen is replaced by a vinyl, aryl, or benzyl group, with the latter being introduced as a halide, diazonium salt, aryl triflate or hypervalent iodo compound.
  • R_X + ⁇ / profession ⁇ / + jj x R vinyl, aryl, or benzyl
  • Typical catalysts for use in the Heck reaction include but are not limited to Pd(dppf)CI 2 /CH 2 CI 2 , [Pd(OAc) 2 ] 3 , trans-PdCI 2 (CH 3 CN) 2 , Pd(C 17 H 14 O) x , and Pd(O)- phosphine complexes such as Pd(PPh 3 ) 4 and trans-PdCI 2 (PPh 3 ) 2 or in situ catalysts such as Pd(OAc) 2 /PPh 3 , and the like.
  • Chelated phosphines with larger bite angles such as Cp 2 Fe(PPh 2 ) 2 and Ph 2 P(CH 2 ) ⁇ PPh 2 are useful with catalysts such as Pd(OAc) 2 , (pi-allyl)Pd complexes, Pd 2 (dba) 3 , Pd(dba) 2 and PdCI 2 , and the like.
  • the presence of phosphines "stabilize" these catalysts.
  • these types of reactions are conducted in polar aprotic mediums (sigma donor type solvents such as acetonitrile, N,N-dimethyl formamide, dimethyl sulfoxide or dimethylacetamide).
  • reaction time and temperature depend on the nature of the organic halide to be activated, lodo derivatives are more reactive and hence auxiliary ligands (phosphines) may not be required.
  • auxiliary ligands phosphines
  • polar solvents such as N 1 N- dimethyl formamide, dimethylacetamide and N-methylpyrrolidine in combination with sodium acetate as a base are especially beneficial.
  • the compounds of formula I can be prepared by a Heck reaction between a compound containing a vinylic hydrogen and a compound containing a vinyl, aryl, or benzyl group which is substituted with a halide, halide, diazonium salt, aryl triflate or hypervalent iodo compound.
  • a Heck reaction between 3-iodo-6-nitro-1-(tetrahydropyran-2-yl)-1H-indazole and 2- vinyl pyridine is accomplished by heating these reactants in the presence of a catalyst such as palladium(ll) acetate (Pd(OAc) 2 ), a ligand such as tri-o-tolylphosphine, a suitable base such as N,N-diisopropylethyl-amine, and a solvent such as DMF to provide 6-nitro-3-((E)-2- pyridin-2-yl-vinyl)-1 -(tetrahydropyran-2-yl)-1 H-indazole.
  • a catalyst such as palladium(ll) acetate (Pd(OAc) 2 )
  • a ligand such as tri-o-tolylphosphine
  • suitable base such as N,N-diisopropylethyl-amine
  • solvent such as DMF
  • the compounds of formula I contain an indazole ring and phenyl ring that are bridged by an amino group.
  • Such amino linked ring structures are obtained by coupling a 6-amino indazole (compound of formual II) with an aryl derivative which is substituted with an activated substituent group X (compound of formula III).
  • Suitable activated substituent groups for X include but are not limited to halides (e.g., chloride, bromide, iodide), hydroxyl derivatives (e.g., triflate, mesylate, and tosylate groups), and diazonium salts.
  • 6-nitroindazole ring compounds can be converted to 6-amino indazole compounds by a reduction.
  • the reduction of nitro groups to amino groups are well known.
  • Metals, such as Fe (iron), Zn (zinc), Sn (tin) and In (indium) can be used with a H + source to reduce a nitro group to an amino group by a sequence of single electron transfer (SET)/protonation reactions.
  • 6-nitro-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1 H-indazole is reduced to the 6-amino compound by treatment with iron metal in the presence of an aqueous solution of ammonium chloride to provide 6-amino-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1 H- indazole.
  • the compounds of formula III are prepared by coupling an aryl amino compound of formula Xl with a carboxylic acid derivative of formula XII:
  • the leaving group Y should be sufficiently reactive in order to be displaced by an aryl amino compound to provide the amido compounds of formula III.
  • suitable leaving groups may be prepared and isolated and/or purified, or reacted without isolation or further purification.
  • suitable leaving groups as Y are halides, aromatic heterocycles, sulfonic acid esters, phosphoric acid esters, anhydrides, or groups derived from the reaction of carboxylic acids, wherein Y is hydroxyl, with reagents such as carbodiimides or carbodiimide species.
  • Suitable leaving groups include, but are not limited to, chloride, bromide, iodide, imidazole, -OC(O)alkyl, -OC(O)aryl, -OC(O)Oalkyl, - OC(O)Oaryl, -OS(O 2 )alkyl, -OS(O 2 )aryl, -OPO(Oaryl) 2 , OPO(Oalkyl) 2 , and those derived from the reaction of carboxylic acids wherein Y is -OH with carbodiimides.
  • Other suitable leaving groups are known and may be found in Humphrey, J. M.; Chamberlin, A.R. Chem. Rev.
  • Compounds of formula XII, where in Y is a halogen can be prepared by reaction of a carboxylic acid (Y is hydroxyl) with a suitable agent such as thionyl chloride or oxalyl chloride in the presence of base to generate an acid chloride. Subsequent reaction of the intermediate acid chloride with an aryl amino compound provides the amido compounds of formula III. 1,3-dimethyl-5-pyrazolecarboxylic acid in ethyl acetate and DMF, and using pyridine as the base, is converted to the acid chloride by treatment with thionyl chloride. Addition of 5- bromo-2-fluoro-aniline to the intermediate acid chloride provides 3-bromo-6-fluoro-1 ,3- dimethylpyrazole-5-carboxamide.
  • the compounds of formula XII are carboxylic acid derivatives that are either commercially available or are readily prepared using known reactions and reagents.
  • the carboxylic acid may be generated through hydrolysis of the corresponding ester.
  • 1.S-dimethyl- ⁇ -pyrazolecarboxylic acid is prepared by the reaction of diethyl oxylate with acetone in the presence of base (sodium methoxide/methanol) to generate the aldol product, ethyl-2,4-dioxovalerate. Acidification and treatment of this aldol product with hydrazine provides the intermediate 3-methyl-pyrazole-5-carboxylic acid methylester. N- methylation of this intermediate with dimethylsulfate followed by base hydrolysis of the methyl ester, provides I .S-dimethyl- ⁇ -pyrazolecarboxylic acid.
  • ethyl-2,4-dioxovalerate is reacted with methyl hydrazine in ethanol to provide the intermediate ethyl ester, which undergoes base hydrolysis to provide 1 ,3-dimethyl ⁇ 5-pyrazolecarboxylic.
  • the compounds of formula Xl are aryl amines that are commercially available or are readily prepared from commercially available aryl precursors using known methods and reagents. Various substituted aryl amines are easily prepared using readily available starting materials by an electrophilic aromatic substitution reaction. As shown below, the nitration/bromination (bromination/nitration) of benzene to meta- or ortho- and para- bromonitrobenzene is exemplary. The relative positions (ortho-, meta-, and para-) of the substituents on a phenyl ring can be controlled by the order in which the various substituents are introduced.
  • bromonitrobenzenes In the preparation of bromonitrobenzenes, nitration followed by bromination provides the meta-substituted bromonitrobenzene, whereas, bromination followed by nitration provides the ortho- and para-substituted bromonitrobenzenes.
  • the ortho- and para- bromonitrobenzene isomers may be separated using known techniques (e.g., chromatography, distillation, recrystallization).
  • aryl nitro group provides the desired aryl amine compounds.
  • reduction of nitro groups to amino groups are well known in the art.
  • Metals such as Fe (iron), Zn (zinc), Sn (tin) and In (indium) can be used with a H + source to reduce a nitro group to an amino group.
  • 5-bromo-2-fluoro-nitrobenzene is reduced to the amino compound by treatment with iron metal in the presence of an aqueous solution of ammonium chloride to provide 5-bromo- 2-fluoro-aniline.
  • the coupling reaction between the compounds of formula Il and the compounds of formula III to provide the compounds of formula IV is accomplished in the presence of a catalyst, a base, and optionally, one or more solvents.
  • the catalyst may be either a palladium or a copper catalyst. Methods that use palladium or copper catalysts to couple arylamines to aryl compounds containing an activated substituent X are well known.
  • the Buchwald-Hartwig reaction is a palladium catalyzed coupling reaction between aryl halides (e.g., chlorides, bromides and iodides) and amines (e.g., alkyl, aryl, and heteroaryl amines) to form arylamines.
  • Pd(O) catalysts A wide variety of homogeneous Pd(O) catalysts can be used for the above reactions.
  • Fully formed Pd(O) compounds such as Pd(PPh 3 ) 4 or catalysts made from precursors such as [Pd(OAc) 2 ] 3 , and Pd(dba) x can be used with suitable phosphines such as triphenylphosphine (PPh 3 ).
  • suitable phosphines such as triphenylphosphine (PPh 3 ).
  • Pd precursor has been PdCI 2 .
  • PPh 3 is not the only phosphine which has been used.
  • palladium catalysts which are useful in the above coupling reaction include but are not limited to Pd(dppf)CI 2 -CH 2 CI 2 , [Pd(P t -Bu 3 )( ⁇ -Br)] 2 , Pd(PCy 3 ) 2 CI 2 , Pd(P(o-tolyl) 3 ) 2 CI 2 , [Pd(P(OPh-2,4-t-Bu)) 2 CI] 2 , FibreCat® 1007 (PCy 2 -fibre/Pd(OAc) 2 ), FibreCat® 1026 (PCy 2 - fibre/PdCI 2 /CH 3 CN), FibreCat® 1001(PPh 2 -fibre/Pd(OAc) 2 ), Pd(dppf)CI 2 , Pd(dppb)CI 2 , Pd(d(dppe)CI 2 , Pd(PPh 3 ) 4 , Pd(PPh 3 )CI 2 , and the like
  • phosphine ligands include but are not limited to: Pd 2 (dba) 3 complexed to a phospine ligand such as 2-(di-f-butylphosphino)biphenyl; Pd(dba) 2 complexed to P(t-Bu) 3 ; Pd(OAc) 2 complexed to (o-biphenyl)P(t-Bu) 2 ; and Pd 2 (dba) 3 complexed to (o- biphenyl)P(t-Cy) 2 .
  • Pd 2 (dba) 3 complexed to a phospine ligand such as 2-(di-f-butylphosphino)biphenyl
  • Pd(dba) 2 complexed to P(t-Bu) 3 Pd(OAc) 2 complexed to (o-biphenyl)P(t-Bu) 2
  • Copper catalysts which are useful in the above coupling reaction include those catalysts in which the copper is complexed with one or more ligands, including but not limited to Cul/ethylene glycol complex; CuBr/DBU complex, Cu(PPh 3 )Br; and Cu(PPh 3 )Br additionally complexed to 1 ,10-phenanthroline or neocuproine (e.g., Cu(phen) (PPh 3 )Br and Cu(neocup)(PPh 3 )Br, respectively), and the like.
  • ligands including but not limited to Cul/ethylene glycol complex
  • CuBr/DBU complex Cu(PPh 3 )Br
  • Cu(PPh 3 )Br additionally complexed to 1 ,10-phenanthroline or neocuproine (e.g., Cu(phen) (PPh 3 )Br and Cu(neocup)(PPh 3 )Br, respectively), and the like.
  • Bases which are useful in the above coupling reaction include but are not limited to potassium carbonate, sodium carbonate, cesium carbonate, sodium f-butoxide, potassium t- butoxide, potassium phenoxide, triethylamine, and the like, or mixtures thereof.
  • Solvents may be used in such coupling reactions including but not limited to toluene, xylenes, diglyme, tetrahydrofuran, dimethylethyleneglycol, and the like, or mixtures thereof.
  • the activated substituent X in the compounds of formula III should be such that it provides sufficient reactivity to react with the compounds of formula Il to provide the compounds of formula IV.
  • Compounds of formula III that contain such activated substituents may be prepared, isolated and/or purified, and subsequently reacted with the compounds of formula II.
  • compounds of formula III with suitable activated substituents may be prepared and further reacted without isolation or further purification with the compounds of formula Il to afford the compounds of formula IV.
  • suitable activated substituent groups for X are halogens (e.g., Cl, Br, and I); derivatized hydroxyl groups (e.g., triflate, mesylate, and tosylate); and diazonium salts.
  • 6-amino-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole is reacted with a catalytic amount of tris(dibenzylideneacetone) dipalladium in the presence of 2-(di-f- butylphosphino)biphenyl, sodium f-butoxide, and 3-bromo-6-fluoro-1 ,3-dimethylpyrazole-5- carboxamide in toluene at 102 0 C to provide 6-(2-fluoro-1 ,3-dimethylpyrazole-5-carboxamide)- 3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1 H-indazole
  • suitable reagents and reaction conditions for deprotecting the N-1 indazole ring nitrogen group, W are well known.
  • suitable reagents include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, para-toluenesulfonic acid, methanesulfonic acid, or Lewis acids such as boron trifluoride etherate. These reactions may be conducted in solvents that are compatible with the specific reaction conditions chosen and will not interfere with the desired transformation.
  • the compounds of formula I may be present in an amorphous state or as one of several polymorph crystalline form, or mixtures thereof.
  • the compound of formula VII (2,5-dimethyl-2H-pyrazole-3-carboxylic acid ⁇ 2-fluoro-5-[3-((E)-2-pyridin-2-yl- vinyl)-1H-indazol-6-ylamino]phenyl ⁇ amide):
  • vm exists in the amorphous state as well as having several polymorph structures.
  • Each crystalline or amorphous form of this compound can be characterized by one or more of the following: X-ray powder diffraction pattern (i.e., X-ray diffraction peaks at various diffraction angles (2 ⁇ )), melting point onset (and onset of dehydration for hydrated forms) as illustrated by endotherms of a Differential Scanning Calorimetry (DSC) thermogram, Raman spectral diagram pattern, aqueous solubility, light stability under International Conference on Harmonization (ICH) high intensity light conditions, and physical and chemical storage stability.
  • DSC Differential Scanning Calorimetry
  • polymorph or amorphous forms of the invention are preferably substantially pure, meaning each polymorph or amorphous form of the compound of formula I includes less than 10%, preferably less than 5%, preferably less than 3%, preferably less than 1% by weight of impurities, including other polymorph or amorphous forms of the compound.
  • the solid forms of the present invention may also exist together in a mixture.
  • Mixtures of polymorphs and/or the amorphous form of the present invention will have X-ray diffraction peaks characteristic of each of the polymorphs and/or amorphous forms present in the mixture.
  • a mixture of two polymorphs will have a powder X-ray diffraction pattern that is a convolution of the X-ray diffraction patterns corresponding to the substantially pure polymorphs.
  • Form I is a substantially pure polymorph and has a powder X-ray diffraction (PXRD) pattern comprising the peaks at diffraction angles (29) of 5.5 and 28.4. More particularly, polymorph Form I has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) of 5.5, 9.5, 10.7, and 28.4. Even more particularly, polymorph Form I has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) essentially the same as shown in Figure 1A. Still more particularly, polymorph Form I is characterized by a Raman spectra essentially the same as shown in Figure 1 C.
  • PXRD powder X-ray diffraction
  • Form Il of the compound of formula VIII is a substantially pure polymorph and has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) of 12.1 and 16.7. More particularly, polymorph Form Il has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) of 12.1 , 13.0, 16.7, and 18.3. Even more particularly, polymorph Form Il has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) essentially the same as shown in Figure 2A. Still more particularly, polymorph Form Il is characterized by a Raman spectra essentially the same as shown in Figure 2C.
  • Form III of the compound of formula VIII is a substantially pure polymorph and has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) of 6.4 and 23.4. More particularly, polymorph Form III has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) of 6.4, 23.4, 25.0, and 27.3. Even more particularly, polymorph Form III has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) essentially the same as shown in Figure 3A. Still more particularly, polymorph Form III is characterized by a Raman spectra essentially the same as shown in Figure 3C.
  • Form IV of the compound of formula VIII is a substantially pure polymorph and has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) of 24.5 and 34.1. More particularly, polymorph Form IV has a PXRD pattern comprising the peaks at diffraction angles (26) of 12.8, 15.8, 24.5, and 34.1. Even more particularly, polymorph Form IV has a PXRD pattern comprising the peaks at diffraction angles (29) essentially the same as shown in Figure 4A. Still more particularly, polymorph Form IV is characterized by a Raman spectra essentially the same as shown in Figure 4C.
  • polymorph Form IV can be characterized by an onset of crystal melting endotherm at about 118 0 C at a scan rate of 10 0 C per minute. Still more particularly, polymorph Form IV has a DSC thermogram essentially the same as shown in Figure 4B.
  • Form V of the compound of formula VIII is a substantially pure polymorph and has a PXRD pattern comprising the peaks at diffraction angles (26) of 8.4 and 26.0. More particularly, polymorph Form V has a PXRD pattern comprising the peaks at diffraction angles (26) of 8.4, 14.2, 22.2, and 26.0. Even more particularly, polymorph Form V has a PXRD pattern comprising the peaks at diffraction angles (26) essentially the same as shown in Figure 5A. Still more particularly, polymorph Form IV is characterized by a Raman spectra essentially the same as shown in Figure 5C. Form Ia of the compound of formula VIII is a substantially pure polymorph and has a
  • polymorph Form Ia has a PXRD pattern comprising the peaks at diffraction angles (26) of 5.5 and 25.2. More particularly, polymorph Form Ia has a PXRD pattern comprising the peaks at diffraction angles (26) of 5.5, 10.6, 18.9, and 25.2. Even more particularly, polymorph Form Ia has a PXRD pattern comprising the peaks at diffraction angles (26) essentially the same as shown in Figure 6A.
  • Form Ib of the compound of formula VIII is a substantially pure polymorph and has a PXRD pattern comprising the peaks at diffraction angles (26) of 10.2 and 13.8. More particularly, polymorph Form Ib has a PXRD pattern comprising the peaks at diffraction angles (26) of 10.2, 13.8, 20.1 , and 26.2. Even more particularly, polymorph Form Ib has a PXRD pattern comprising the peaks at diffraction angles (26) essentially the same as shown in Figure 7A. Still more particularly, polymorph Form Ib is characterized by a Raman spectra essentially the same as shown in Figure 7C.
  • Form Ha of the compound of formula VIII is a substantially pure polymorph and has a PXRD pattern comprising the peaks at diffraction angles (26) of 12.8 and 22.9. More particularly, polymorph Form Ha has a PXRD pattern comprising the peaks at diffraction angles (26) of 12.8, 16.0, 22.9, and 31.2. Even more particularly, polymorph Form Ha has a PXRD pattern comprising the peaks at diffraction angles (26) essentially the same as shown in Figure 8A.
  • Form lib of the compound of formula VIlI is a substantially pure polymorph and has a PXRD pattern comprising the peaks at diffraction angles (26) of 14.3 and 19.0. More particularly, polymorph Form Hb has a PXRD pattern comprising the peaks at diffraction angles (26) of 7.9, 14.3, 19.0, and 27.0. Even more particularly, polymorph Form lib has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) essentially the same as shown in Figure 9A. Still more particularly, polymorph Form IV is characterized by a Raman spectra essentially the same as shown in Figure 9C.
  • Form Ilia of the compound of formula VIII is a substantially pure polymorph and has a PXRD pattern comprising the peaks at diffraction angles (29) of 24.9 and 36.2. More particularly, polymorph Form Ilia has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) of 14.7, 21.0, 24.9, and 36.2. Even more particularly, polymorph Form MIa has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) essentially the same as shown in Figure 1OA.
  • Form INb of the compound of formula VIII is a substantially pure polymorph and has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) of 6.8 and 14.5. More particularly, polymorph Form IMb has a PXRD pattern comprising the peaks at diffraction angles (29) of 6.8, 14.5, 20.8, and 24.8. Even more particularly, polymorph Form MIb has a PXRD pattern comprising the peaks at diffraction angles (29) essentially the same as shown in Figure 11 A. Still more particularly, polymorph Form MIb is characterized by a Raman spectra essentially the same as shown in Figure 11 C.
  • Form IVa of the compound of formula VIM is a substantially pure polymorph and has a PXRD pattern comprising the peaks at diffraction angles (29) of 13.5 and 32.5. More particularly, polymorph Form IVa has a PXRD pattern comprising the peaks at diffraction angles (29) of 13.5, 15.8, 27.0, and 32.5. Even more particularly, polymorph Form IVa has a PXRD pattern comprising the peaks at diffraction angles (29) essentially the same as shown in Figure 12A. Still more particularly, polymorph Form IVa has an onset of dehydration endotherm at about 63 °C and an onset of crystal melting endotherm at about 123 0 C at a scan rate of 10 0 C per minute. Still further, polymorph Form IVa has a DSC thermogram essentially the same as shown in Figure 12B.
  • Form Va of the compound of formula VIM is a substantially pure polymorph and has a
  • polymorph Form Va has a PXRD pattern comprising the peaks at diffraction angles (29) of 19.2 and 33.9. More particularly, polymorph Form Va has a PXRD pattern comprising the peaks at diffraction angles (29) of 11.5, 19.2, 24.4, and 33.9. Even more particularly, polymorph Form Va has a PXRD pattern comprising the peaks at diffraction angles (29) essentially the same as shown in Figure 13A. Still more particularly, polymorph Form Va is characterized by a Raman spectra essentially the same as shown in Figure 13C.
  • Form Vl of the compound of formula VIM is a substantially pure polymorph and has a PXRD pattern comprising the peaks at diffraction angles (29) of 7.7 and 26.8. More particularly, polymorph Form Vl has a PXRD pattern comprising the peaks at diffraction angles (29) of 7.7, 12.9, 18.5, and 26.8. Even more particularly, polymorph Form Vl has a PXRD pattern comprising the peaks at diffraction angles (29) essentially the same as shown in Figure 14A. Still more particularly, polymorph Form Vl is characterized by a Raman spectra essentially the same as shown in Figure 14C.
  • the amorphous form of the compound of formula VIII has a PXRD pattern exhibiting a broad peak at diffraction angles (2 ⁇ ) ranging from 4 to 40° without any of the sharp peaks characteristic of a crystalline form. More particularly, the amorphous form is characterized by having a PXRD pattern essentially the same as shown in Figure 15A. Even more particularly, the amorphous form is characterized by a Raman spectra comprising shift peaks (cm '1 ) essentially the same as shown in Figure 15B.
  • a solid form of the compound of formula VIII exists as a mixture comprising at least two of the following solid forms: polymorph Forms I 1 II, III, IV, V, Ia, Ib, Ha, lib, Ilia, IHb, IVa, Va, Vl, and an amorphous form.
  • Form lbm-2 of the compound of formula VIII is a substantially pure polymorph of the compound of formula VIII, which is a mixture of Forms Ib and Vl, and has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) of 12.9 and 13.8. More particularly, polymorph Form lbm-2 has a PXRD pattern comprising the peaks at diffraction angles (26) of 12.9, 13.8, 20.1 , and 26.8. Even more particularly, polymorph Form lbm-2 has a PXRD pattern comprising the peaks at diffraction angles (2 ⁇ ) essentially the same as shown in Figure 16.
  • indazole compounds of formula I which are useful as modulators and/or inhibitors of protein kinases. These compounds, prepared by the methods of the present invention, are useful as anti-angiogenesis agents and as agents for modulating and/or inhibiting the activity of protein kinases, thus providing treatments for cancer or other diseases associated with cellular proliferation mediated by protein kinases.
  • the X-ray powder diffraction pattern for each polymorph or amorphous form of the invention was measured on a Shimadzu XRD-6000 X-ray diffractometer equipped with a Cu X-ray source operated at 40 kV and 50 mA. Samples were placed in a sample holder and then packed and smoothed with a glass slide. During analysis, the samples were rotated at 60 rpm and analyzed from angles of 4 to 40° ( ⁇ -2 ⁇ ) at 57min with a 0.04° step or at 27min with a 0.02° step. If limited material was available, samples were placed on a silicon plate (zero background) and analyzed without rotation.
  • the peak positions (2 ⁇ ) will show some inter-apparatus variability, typically as much as 0.1°. Accordingly, where the solid forms of the present invention are described as having a powder X-ray diffraction pattern essentially the same as that shown in a given figure, the term "essentially the same" is intended to encompass such inter-apparatus variability in diffraction peak positions.
  • the DSC thermographs were obtained using a Mettler Toledo DSC821 e instrument at a scan rate of 10 °C/min over a temperature range of 30-250 0 C. Samples were weighed into 40 ⁇ l aluminum crucibles that were sealed and punctured with a single hole. The extrapolated onset of melting temperature and, where applicable, the onset of dehydration temperature, were calculated.
  • the endotherms exhibited by the compounds of the invention may vary (by about 0.01-5 0 C for crystal polymorph melting and by about 0.01-20 0 C for polymorph dehydration) above or below the endotherms depicted in the appended figures.
  • Factors responsible for such variance include the rate of heating (i.e., the scan rate) at which the DSC analysis is conducted, the way the DSC onset temperature is defined and determined, the calibration standard used, instrument calibration, the relative humidity and the chemical purity of the sample.
  • the observed endotherms may also differ from instrument to instrument; however, it will generally be within the ranges defined herein provided the instruments are calibrated similarly.
  • Raman scattering spectra were obtained by using a Fourier transform Raman spectrophotometer Kaiser Optical Instruments, Ramen RXN1 -785.
  • the excitation light source was an Invictus NIR Laser operating at 785 nm wavelength.
  • the detector was an Andor CCD. The resolution was 34 cm "1 .
  • DMF means N,N-dimethyl formamide
  • THF means tetrahydrofuran
  • Et means ethyl
  • Ac means acetyl
  • Me means methyl
  • Ph means phenyl
  • HI means hydrochloric acid
  • EtOAc means ethyl acetate
  • Na 2 CO 3 means sodium carbonate
  • NaHCO 3 means sodium hydrogen carbonate (sodium bicarbonate)
  • NaOH means sodium hydroxide
  • Na 2 S 2 O 3 means sodium thiosulfate
  • NaCI means sodium chloride
  • Et 3 N means triethylamine
  • H 2 O means water
  • KOH means potassium hydroxide
  • K 2 CO 3 means potassium carbonate
  • MeOH means methanol
  • i-PrOAc means isopropyl acetate
  • MgSO 4 means isopropyl acetate
  • MgSO 4 means isopropyl acetate
  • MgSO 4 means isoprop
  • 6-Nitroindazole 45.08 Kg is dissolved in N,N-dimethyl formamide (228 Kg) and powdered potassium carbonate (77 Kg) is added while the solution temperate is maintained at ⁇ 3O 0 C.
  • the mixture is then added to a solution of sodium thiosulfate (68 Kg) and potassium carbonate (0.46 Kg) dissolved in water (455 Kg) while the solution temperature is maintained ⁇ 3O 0 C.
  • the mixture is agitated for 1.5 hours at 22 0 C.
  • Water (683 Kg) is added which precipitates solids and the slurry is agitated for 1 to 2 hours at 22 0 C.
  • 3-iodo-6-nitroindazole (74.6 Kg) is dissolved in methylene chloride (306 Kg) and tetrahydrofuran (211 L), and methanesulfonic acid (3.0 Kg) is carefully added. (Caution: residual sodium bicarbonate may cause CO 2 to be evolved. Monitor the pressure in the reactor).
  • a solution of DHP (55 Kg) in methylene chloride (97 Kg) is added over 5 to 6 hours while the reaction temperature is maintained at ⁇ 22 0 C. The mixture is agitated at 22 0 C for 2 to 6 hours (until the reaction is complete by HPLC).
  • the mixture is then carefully added to an aqueous solution of 10% NaHCO 3 (37 Kg of NaHCO 3 dissolved in 370 Kg water) while the solution temperature is maintained at 22 0 C. (Caution: CO 2 is evolved. Monitor the pressure in the reactor).
  • the mixture is agitated for 1 hour at 22 0 C and the layers separated.
  • the organic layer is washed with an aqueous solution of 10% NaCI (407 Kg) and the layers separated.
  • the organic layer is concentrated at 55 0 C and atmospheric pressure to cut the volume to half (ca. 500 L), then under reduced pressure to remove the remaining solvents.
  • the concentrate (ca.138 L) is co-evaporated with acetonitrile (1 x 224 Kg, 1 x 75 Kg, 1 x 60 Kg) at 55 0 C under reduced pressure until the final volume is ca. 80 L.
  • the resulting slurry is diluted with acetonitrile (60 Kg) and is agitated for 8 hours at -5 0 C.
  • the slurry is filtered, and the solids are rinsed with cold acetonitrile (15 Kg).
  • the solids are dried at room temperature under reduced pressure to provide 77.6 Kg of 3-iodo-6-nitro-1-(tetrahydropyran-2-yl)-1H- indazole (80.5% yield with a purity of 95% by HPLC).
  • 3-iodo-6-nitro-1-(tetrahydropyran-2-yl)-1 H-indazole (77 Kg) is added to a solution of 2-vinyl pyridine (31 Kg), N,N-diisopropylethylamine (51 Kg), and tri-o-tolylphosphine (5.414 Kg) in N,N-dimethyl formamide (163 Kg).
  • Pd(OAc) 2 1.503 Kg
  • the mixture is then cooled to 45 0 C and isopropanol (248 Kg) is added.
  • the mixture is agitated for 30 minutes at 45 0 C, diluted with water (1 ,238 L), and the mixture is agitated at 22 0 C for 1 to 2 hours.
  • the resulting slurry is filtered, rinsed with water (77 L), and the solids are combined with isopropanol (388 Kg).
  • the mixture is agitated for 30 to 90 minutes at 55 0 C, then for 30 to 90 minutes at 1O 0 C, filtered, and the solids are washed with cold (ca. 1O 0 C) isopropanol (2 x 30 L).
  • 6-nitro-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole (61.4 Kg) is dissolved in an aqueous solution of ammonium chloride (71.4 Kg of NH 4 CI in 257 Kg water) and ethanol (244 Kg) is added. Iron powder (39 Kg) is added and the mixture is agitated for 2 to 8 hours at 5O 0 C (until the reaction is complete by HPLC). (Add more iron powder (ca. 9.8 Kg) if the reaction is not complete after 8 hours). The mixture is then cooled to 22 0 C and tetrahydrofuran (1,086 Kg) is added.
  • the mixture is agitated for 1 hour at 22 0 C, and filtered through diatomaceous earth (ca. 5 Kg).
  • the cake is rinsed with tetrahydrpfuran (214 Kg), and the filtrate is concentrated at 5O 0 C under reduced pressure to a volume of ca. 305 L.
  • the concentrate is cooled to 22 0 C, diluted with water (603 Kg), and agitated at 22 0 C for 1 hour.
  • 5-Bromo-2-fluoro-nitrobenzene (698 g) is dissolved in 95% ethanol (0.90 L) and is added to a mixture of iron powder (711 g) in a saturated aqueous ammonium chloride solution (2.0 L). The reaction mixture is agitated for 24 hours at 7O 0 C (until the reaction is complete by HPLC). The reaction mixture is then cooled to room temperature, filtered through Celite, and the filtrate is evaporated under reduced pressure. The residue is extracted with ethyl acetate (2 L) and water (2 L) and the layers separated. The aqueous layer is extracted with ethyl acetate (1 L).
  • Diethyl oxalate (3.4 L) is dissolved in acetone (1.84 L) and the solution is added drop- wise over 7 hours at O 0 C to a solution of 25% sodium methoxide in methanol (5.72 L) dissolved in anhydrous methanol (8 L). Throughout the process, the internal temperature should never exceed 20 0 C. Drop-wise addition is imperative, fast addition is detrimental to the reaction. The reaction mixture is stirred at 0 0 C for 14 hours. Concentrated HCI (2.1 L) is added drop-wise over 3 hours at O 0 C to the reaction mixture. Throughout the process, the internal temperature never exceeded 20 0 C. Hydrazine monohydrate (1.21 L) is added drop- wise in over 5 hours at O 0 C to the reaction mixture.
  • the internal temperature is maintained approximately at room temperature. Throughout the process, the internal temperature never exceeded 24 0 C.
  • the resulting mixture is allowed to stir for 18 hours at 22 0 C.
  • the mixture is filtered and the filtrate is concentrated under reduced pressure to 7 L.
  • the concentrate is diluted with ethyl acetate (16 L) and water (12 L), the mixture is extracted, and the layers are separated.
  • the organic layer is dried over MgSO 4 , filtered, and the solvents removed under reduced pressure to provide 2.61 Kg of 3-methyl-pyrazole-5-carboxylic acid methylester (75 % yield with a purity of 95%).
  • 3, ⁇ -dimethyl-pyrazole- ⁇ -carboxylic acid methylester (5.14 Kg) is added to an aqueous solution of 20% sodium hydroxide (10 L) at O 0 C.
  • the reaction mixture is stirred at room temperature for 18 hours and cooled to O 0 C.
  • Concentrated hydrochloric acid (4.2 L) is then added to the reaction mixture in over 7 hours.
  • the resulting thick slurry is stirred at room temperature for 18 hours.
  • Ethyl-2,4-dioxovalerate (Kg) is added to a solution of methyl hydrazine (L) in ethanol (L) and heated to 6O 0 C for 18 hours to provide the intermediate 3,5-dimethyl-pyrazole-5- carboxylic acid ethylester.
  • Example 7 Preparation of S-Bromo- ⁇ -fluoro-I.S-dimethylpyrazole- ⁇ -carboxamide
  • reaction mixture is stirred for 18 hours at 35 0 C, cooled to room temperature, diluted with ethyl acetate (500 mL) and water (750 mL), extracted, and the layers are separated.
  • the aqueous layer is extracted with ethyl acetate (500 mL), and the combined organic layers are dried over MgSO 4 , filtered, and concentrated under reduced pressure.
  • 6-amino-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1 H-indazole (50.0 g), 3- bromo-6-fluoro-1,3-dimethylpyrazole-5-carboxamide (48.8 g), 2-(di-f-butylphosphino)biphenyl (2.42 g), sodium f-butoxide (19.30 g), tris(dibenzylideneacetone) dipalladium (2.85 g) and toluene (500 mL) are combined and agitatede for 18 hours at 102 0 C).
  • the reaction mixture is then cooled to 4O 0 C, and THF (500 mL) and 10% cysteine on silica gel (250 g) is added.
  • THF 500 mL
  • 10% cysteine on silica gel 250 g
  • the resulting mixture is stirred for 24 hours and filtered through a pad of Celite (100 g).
  • the pad is washed with THF (500 mL) and the combined filtrates are concentrated under reduced pressure to a volume of 1 L.
  • the concentrate is stirred with 10% cysteine on silica gel (250 g) for 48 hours and filtered through a pad of Celite (100 g).
  • 6-(2-fluoro-1 ,3-dimethylpyrazole-5-carboxamide)-3-((E)-2-pyridin-2-yl-vinyl)-1- (tetrahydropyroan-2-yl)-1 H-indazole (77.67 g) and p-toluenesulfonic acid monohydrate (78.76 g) are dissolved in methanol (500 mL) and agitated for 18 hours at 68 0 C.
  • the resulting orange slurry is diluted with isopropanol (500 mL) and agitated for 2 hours at room temperature.
  • the mixture is filtered, and the solids are washed with isopropanol (500 mL).
  • the solids are suspended isopropanol (500 mL), and a solution of K 2 CO 3 (97.8 g) in water (700 mL) is added.
  • Example 10 Polymorph Form I of 6-(3-Bromo-6-fluoro-1.3-dimethylpyrazole-5-carboxamide)- 3-((E)-2-pyridin-2-yl-vinyl)-1 H-indazole
  • Polymorph Form I an anhydrous form of the compound of formula VIII, is prepared by slurrying the compound of formula VIII (155 mg) in ethanol (5 mL) and heating to reflux for 30 minutes. The sample is slowly cooled to 23°C to provide a solid precipitate. The solids are collected by filtration and dried at 85 0 C under high vacuum. Form I was confirmed by X- ray diffraction and the HPLC purity was >98%. Form I has an aqueous solubility of about 39 ⁇ g/mL at pH 2 and about 0.4 ⁇ g/mL at pH 7.4. Form I is light-stable under ICH high intensity light conditions and chemically stable at 80 0 C and 40°C/75%RH for at least 14 days.
  • Form I is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (20): 4.80, 5.49, 7.06, 7.90, 9.52, 10.67, 12.33,
  • Figure 1A provides an X-ray powder diffraction pattern for Form I.
  • the DSC thermogram for Form I shown in Figure 1B, indicates an onset of crystal melting endotherm at about 183 0 C, at a scan rate of 10°C/minute.
  • the Raman spectral diagram for Form I shown in Figure 1C, includes Raman Shift peaks (cm '1 ) at approximately 993, 1265, 1323, 1377, 1394, 1432, 1465, 1482, 1563, 1589, and 1640.
  • Example 11 Polymorph Form Il of 6-(3-Bromo-6-fluoro-1.3-dimethylpyrazole-5-carboxamide)- 3-((E)-2-pyridin-2-yl-vinyl)-1 H-indazole
  • Polymorph Form II an anhydrous form of the compound of formula VIII, is prepared by dissolving the compound of formula VIII (Example 10, Form I) in THF at 60 0 C, and re- crystallizing by gradual addition of hexanes.
  • Form Il was confirmed by X-ray diffraction (HPLC purity >98%).
  • Form Il has an aqueous solubility of about 19 ⁇ g/mL at pH 2 and about 0.7 ⁇ g/mL at pH 7.4.
  • Form Il is light stable under ICH high intensity light conditions.
  • Form Il is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (2 ⁇ ): 4.65, 6.9200, 7.36, 7.76, 9.81 , 11.41 , 12.08, 12.60, 13.03, 13.72, 14.24, 14.72, 16.06, 16.66, 17.80, 18.32, 18.80, 19.68, 20.32, 21.05, 21.89, 22.64, 23.00, 23.60, 25.45, 26.30, 27.18, 28.34, 29.04, 30.21 , 31.14, 32.24, 34.14, 34.91 , 36.97, 39.21 , and 39.92.
  • Figure 2A provides an X-ray powder diffraction pattern for Form II.
  • the DSC thermogram for Form II shown in Figure 2B, indicates an onset of crystal melting endotherm at about 195°C, at a scan rate of 10°C/minute.
  • Example 12 Polymorph Form III of 6-(3-Bromo-6-fluoro-1.3-dimethylpyrazole-5- carboxamide)-3-((E)-2-pyridin-2-yl-vinyl)-1H-indazole
  • Polymorph Form III an anhydrous form of the compound of formula VIII, is prepared by slurrying the compound of formula VIII (Example 10, Form I) in light mineral oil at 192 0 C for about 1.5 hours. The mixture is allowed to cool to room temperature and the solids are washed with hexanes, filtered, and dried at 50 0 C under vacuum. Form III was confirmed by
  • Form III has an aqueous solubility of about 10 ⁇ g/mL at pH 2 and about 0.6 ⁇ g/mL at pH 7.4. Form III is light-stable under ICH high intensity light conditions.
  • Form III is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (26): 6.40, 6.87, 7.36, 9.73, 10.43, 13.20, 13.72, 14.04, 14.65, 15.20, 15.80, 17.60, 18.56, 19.56, 20.16, 20.56, 21.49, 21.96, 22.92, 23.40, 24.08, 24.98, 25.64, 27.32, 27.72, 28.35, 29.08, 29.56, 30.12, 30.58, 31.53, 33.58, 35.01 , 36.84, 37.24, 37.60, and 39.51.
  • Figure 3A provides an X-ray powder diffraction pattern for Form III.
  • the DSC thermogram for Form III shown in Figure 3B, indicates an onset of crystal melting endotherm at about 21O 0 C, at a scan rate of 10°C/minute.
  • the Raman spectral diagram for Form III shown in Figure 3C, includes Raman Shift peaks (cm '1 ) at approximately 991, 1261 , 1379, 1431 , 1589, and 1634.
  • Example 13 Polymorph Form IV of 6-(3-Bromo-6-fluoro-1.3-dimethylpyrazole-5- carboxamide)-3-((E)-2-pyridin-2-yl-vinyl)-1 H-indazole
  • Form IV an anhydrous form of the compound of formula VIM, is prepared by dissolving the compound of formula VIII (crude material from synthesis) in ethyl acetate and ethanol, and recrystallizing by addition of 1:1 NaHC0 3 :Water. Form IV was confirmed by X- ray diffraction (HPLC purity>99%). Form IV has an aqueous solubility of about 7 ⁇ g/mL at pH
  • Form IV is light stable under ICH high intensity light conditions.
  • Form IV is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (29): 4.85, 7.95, 9.85, 11.51 , 12.80, 13.53, 14.56,
  • Figure 4A provides an X-ray powder diffraction pattern for Form IV.
  • the DSC thermogram for Form IV shown in Figure 4B, indicates an onset of crystal melting endotherm at about 118 0 C, at a scan rate of 10°C/minute.
  • the Raman spectral diagram for Form IV shown fn Figure 4C, includes Raman Shift peaks (cr ⁇ f 1 ) at approximately 998, 1269, 1314, 1340, 1371, 1436, 1463, 1483, 1562, 1592, and 1644.
  • Example 14 Polymorph Form V of 6-(3-Bromo-6-fluoro-1.3-dimethylpyrazole-5-carboxamide)- 3-((E)-2-pyridin-2-yl-vinv ⁇ -1 H-indazole
  • Form V an anhydrous form of the compound of formula VIII, is prepared by slurrying Form IV solids in heavy mineral oil at 130 0 C, and then 18O 0 C for about 1.5 hours, followed by hexane wash and filtration. The solids are collected by filtration, washed with hexanes, and dried under vacuum. Form V was confirmed by X-ray diffraction (HPLC purity >99%).Form V has an aqueous solubility of about 8 ⁇ g/mL at pH 2 and about 0.2 ⁇ g/mL at pH 7.4.
  • Form V is light stable under ICH high intensity light conditions
  • Form V is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (20): 4.23, 8.38, 11.74, 12.00, 12.47, 12.95, 13.58, 14.17, 15.15, 16.76, 16.96, 17.44, 17.92, 18.28, 18.70, 19.37, 20.26, 21.16, 21.62, 21.84, 22.16, 22.54, 23.28, 23.64, 24.17, 24.84, 25.12, 25.58, 25.98, 26.48, 27.02, 28.16, 28.54, 29.14, 29.89, 31.40, 32.23, 32.66, and 39.68.
  • Figure 5A provides an X-ray powder diffraction pattern for Form V.
  • the DSC thermogram for Form V shown in Figure 5B, indicates an onset of crystal melting endotherm at about 210 0 C, at a scan rate of 10°C/minute.
  • the Raman spectral diagram for Form V shown in Figure 5C, includes Raman Shift peaks (cm "1 ) at approximately 989, 1230, 1298, 1374, 1433, 1466, 1481 , 1562, 1586, and 1642.
  • Example 15 Polymorph Form Ia of 6-(3-Bromo-6-fluoro-1.3-dimethylpyrazole-5- carboxamide)-3-((E)-2-pyridin-2-yl-vinyl)-1 H-indazole
  • Form Ia a hydrate form of the compound of formula VIII, is prepared by slurrying Form I in water (approximately 20-40 mg/mL) at ambient temperature for seven days. Form Ia was confirmed by X-ray diffraction (HPLC purity > 99%). Form Ia is light-stable under ICH high intensity light conditions.
  • Form Ia is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (2 ⁇ ): 4.84, 5.49, 7.07, 7.90, 9.55, 10.60, 10.96, 11.48, 12.20, 12.72, 13.48, 14.10, 14.56, 15.78, 17.54, 18.08, 18.52, 18.88, 19.44, 21.11 , 21.93, 22.48, 23.06, 23.72, 24.20, 24.48, 25.20, 25.56, 26.12, 26.72, 27.12, 27.78, 28.75, 30.36, 30.68, 31.20, 31.64, 32.04, 34.64, 34.97, 36.16, 36.60, 36.92, 37.24, 37.68, 38.12, 38.48, and 39.80.
  • Figure 6A provides an X-ray powder diffraction pattern for Form Ia.
  • the DSC thermogram for Form Ia shown in Figure 6B, indicates an onset of dehydration endotherm at about 60 0 C and an onset of crystal melting endotherm at about 185°C, at a scan rate of 10°C/minute.
  • Example 16 Polymorph Form Ib of 6-(3-Bromo-6-fluoro-1.3-dimethylpyrazole-5- carboxamide)-3-((E)-2-pyridin-2-yl-vinyl)-1 H-indazole
  • Form Ib a mono-hydrate of the compound of formula VIII, is prepared by slurrying Form I in water (approximately 20-40 mg/mL) at 90 0 C for three days, or by crystallization from ethanohwater at greater than 65°C. Form Ib is also obtained by crystallization from ethanol:water at 65 0 C. Form Ib was confirmed by X-ray diffraction (HPLC purity > 99%). Form Ib is physically and chemically stable for at least three months at 60 0 C and 40°C/75%RH and is also light-stable under ICH high intensity light conditions
  • Form Ib is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (20): 7.93, 10.23, 11.04, 13.12, 13.79, 14.88, 15.24,
  • Figure 7A provides an X-ray powder diffraction pattern for Form Ib.
  • the DSC thermogram for Form Ib indicates an onset of dehydration endotherm at about 67°C and an onset of crystal melting endotherm at about 179°C, at a scan rate of 10°C/minute.
  • the Raman spectral diagram for Form Ib shown in Figure 7C, includes Raman Shift peaks (cm "1 ) at approximately 964, 1002, 1239, 1266, 1372, 1470, 1558, and 1641.
  • Example 17 Polymorph Form Ha of 6-(3-Bromo-6-fluoro-1,3-dimethylpyrazole-5- carboxamide)-3-((E)-2-pyridin-2-yl-vinyl)-1 H-indazole
  • Form Na a mono-hydrate of the compound of formula VIII, is prepared by slurrying Form Il in water (approximately 20-40 mg/mL) at ambient temperature for seven days.
  • Form Ha was confirmed by X-ray diffraction (HPLC purity > 99%).
  • Form Ma is light stable under ICH high intensity light conditions.
  • Form Na is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (26): 4.77, 7.64, 8.80, 9.82, 11.41 , 12.75, 13.48, 14.23, 15.96, 16.64, 17.68, 18.76, 21.67, 22.85, 25.38, 27.16, 28.24, 30.12, 31.23, 32.16,
  • Figure 8A provides an X-ray powder diffraction pattern for Form Na.
  • the DSC thermogram for Form Na shown in Figure 8B, indicates an onset of dehydration endotherm at about 51 0 C and an onset of crystal melting endotherm at about 194°C, at a scan rate of 10°C/minute.
  • Example 18 Polymorph Form Hb of 6-(3-Bromo-6-fluoro-1,3-dimethylpyrazole-5- carboxamide)-3-((E)-2-pyridin-2-yl-vinyl)-1 H-indazole
  • Form Hb which is a di-hydrate of the compound of formula VIII, is prepared by slurrying Form Il in water (approximately 20-40 mg/mL) at 90 0 C for three days and then ambient temperature for 17 days.
  • Form lib is confirmed by X-ray diffraction.
  • Form lib is light stable under ICH high intensity light conditions.
  • Form lib is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (2 ⁇ ): 4.80, 7.86, 8.73, 11.44, 12.70, 13.41 , 14.33,
  • Figure 9A provides an X-ray powder diffraction pattern for Form Hb.
  • the DSC thermogram for Form lib indicates an onset of dehydration endotherm at about 64°C and an onset of crystal melting endotherm at about 197 0 C, at a scan rate of 10°C/minute.
  • the Raman spectral diagram for Form lib shown in Figure 9C, includes Raman Shift peaks (cm "1 ) at approximately 993, 1265, 1362, 1431 , 1464, 1561, 1589, and 1639.
  • Example 19 Polymorph Form HIa of 6-(3-Bromo-6-fluoro-1.3-dimethylpyrazole-5- carboxamide)-3-((E)-2-pyridin-2-yl-vinyl)-1 H-indazole
  • Form Ilia a di-hydrate of the compound of formula VIII, is prepared by slurrying Form
  • Form III in water (approximately 20-40 mg/mL) at ambient temperature for seven days, or by placing Form III in 93% relative humidity at ambient temperature for ten days.
  • Form Ilia is confirmed by X-ray diffraction.
  • Form IMa is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (2 ⁇ ): 6.81, 7.36, 8.71, 9.37, 9.80, 10.51 , 13.31 ,
  • Figure 10A provides an X-ray powder diffraction pattern for Form Ilia.
  • Example 20 Polymorph Form MIb of 6-(3-Bromo-6-fluoro-1 ,3-dimethylpyrazole-5- carboxamide)-3-((E)-2-pyridin-2-yl-vinyl)-1 H-indazole
  • Form IMb an anhydrous form of the compound of formula VIM, is prepared by drying
  • Form Ilia (Example 10) at 5O 0 C under vacuum.
  • Form INb was confirmed by X-ray diffraction.
  • Form IMb is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (2 ⁇ ): 6.28, 6.84, 7.36, 8.66, 9.66, 13.13, 13.80,
  • Figure 11A provides an X-ray powder diffraction pattern for Form IMb.
  • the DSC thermogram for Form IMb shown in Figure 11 B, indicates an onset of crystal melting endotherm at about 210 0 C, at a scan rate of 10°C/minute.
  • the Raman spectral diagram for Form IHb shown in Figure 11C, includes Raman
  • Example 21 Polymorph Form IVa of 6-(3-Bromo-6-fluoro-1,3-dimethylpyrazole-5- carboxamide)-3-((E)-2-pyridin-2-yl-vinyl)-1 H-indazole
  • Form IVa a di-hydrate of the compound of formula VIII, is prepared by slurrying Form
  • Form IV in water (approximately 20-40 mg/mL) at ambient temperature for seven days.
  • Form IVa is light-stable under ICH high intensity light conditions.
  • Form IVa is confirmed by X-ray diffraction and DSC.
  • Form IVa is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (29): 4.85, 7.95, 9.85, 11.51 , 12.80, 13.53, 14.56, 14.92, 15.80, 16.32, 17.43, 18.08, 18.44, 19.31, 20.08, 21.08, 21.61 , 22.64, 23.24, 23.84, 24.48, 25.08, 26.24, 27.02, 27.92, 28.76, 30.12, 30.72, 31.40, 32.52, 34.07, 37.48, and 38.20.
  • Figure 12A provides an X-ray powder diffraction pattern for Form Mb.
  • the DSC thermogram for Form IVa shown in Figure 12B, indicates an onset of dehydration endotherm at about 63°C and an onset of crystal melting endotherm at about 123°C, at a scan rate of 10°C/minute.
  • Example 22 Polymorph Form Va of 6-(3-Bromo-6-fluoro-1.3-dimethylpyrazole-5- carboxamide)-3-((E)-2-pyridin-2-yl-vinyl)-1H-indazole Form Va, a di-hydrate form of the compound of formula VIII, is prepared by slurrying
  • Form V in water (approximately 20-40 mg/mL) at ambient temperature for seven days.
  • Va is light-stable under ICH high intensity light conditions. Form Va is confirmed by X-ray diffraction.
  • Form Va is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (2 ⁇ ): 4.26, 4.82, 7.92, 8.42, 8.96, 11.45, 12.70,
  • Figure 13A provides an X-ray powder diffraction pattern for Form Va.
  • the DSC thermogram for Form Va shown in Figure 13B, indicates an onset of dehydration endotherm at about 74°C and an onset of crystal melting endotherm at about
  • the Raman spectral diagram for Form Va shown in Figure 13C, includes Raman
  • Shift peaks (cm "1 ) at approximately 989, 1228, 1298, 1372, 1430, 1465, 1561, 1584, and 1641.
  • Example 23 Polymorph Form Vl of 6-(3-Bromo-6-fluoro-1.3-dimethylpyrazole-5- carboxamide)-3-((E)-2-pyridin-2-yl-vinyl)-1H-indazole
  • Form Vl an anhydrous form of the compound of formula VIII, is prepared by dehydration of Form Ib, such as by heating Form Ib at 140 c C for 10 minutes.
  • Form Vl was confirmed by X-ray diffraction.
  • Form Vl is very hygroscopic and can be readily converted back to Form Ib under ambient humidity.
  • Form Vl is characterized by an X-ray powder diffraction pattern with peaks at the following approximate diffraction angles (2 ⁇ ): 7.74, 10.00, 11.56, 12.85, 15.56, 16.04, 17.80,
  • Figure 14A provides an X-ray powder diffraction pattern for Form Vl.
  • the DSC thermogram for Form Vl shown in Figure 14B, indicates an onset of crystal melting endotherm at about 179°C, at a scan rate of 10°C/minute.
  • the Raman spectral diagram for Form Vl shown in Figure 14C, includes Raman Shift peaks (cm "1 ) at approximately: 965, 993, 1201 , 1230, 1267, 1320, 1368, 1412, 1426, 1469, 1557, 1587, and 1647.
  • Example 24 Polymorph Form lbm-2 of 6-(3-Bromo-6-fluoro-1.3-dimethylpyrazole-5- carboxamide)-3-((E)-2-pyridin-2-yl-vinyl)-1H-indazole
  • Form lbm-2 which is a mixture of polymorph Form Ib and Form Vl of the compound of formula VIII, is prepared by heating Form Ib (Example 7) at 50 0 C under vacuum.
  • Form lbm-2 is confirmed by X-ray diffraction to be a mixture of polymorph Form Ib and Form Vl.
  • Example 25 Amorphous Form of 6-(3-Bromo-6-fluoro-1.3-dimethylpyrazole-5-carboxamide)- 3-((E)-2-pyridin-2-yl-vinyl)-1 H-indazole
  • the amorphous form of the compound of formula VII is prepared by drop-wise dilution in water (approximately 1:10 ratio) of the compound of formula VIII in polyethylene glycol 400 solution, or roto-vaporation of the compound of formula VIII in methanol or THF solution, or lyophilization of the compound of formula VIII in t-butanol solution.
  • the X-ray powder diffraction pattern of the amorphous form is characterized by a typical amorphous broad hump-peak from 4 to 40°, without any sharp peaks characteristic of crystalline forms.
  • Figure 15A provides an X-ray powder diffraction pattern for the amorphous form.
  • the Raman spectral diagram for the amorphous form shown in Figure 15B, includes Raman Shift peaks (cm "1 ) at approximately 995, 1265, 1366, 1435, 1468, 1562, 1589, and 1640.
  • Example 26 Mixtures of 6-(3-Bromo-6-fluoro-1,3-dimethylpyrazole-5-carboxamide)-3-((E)-2- pyridin-2-yl-vinyl)-1 H-indazole
  • Form lbm-2 is a meta-stable form that is a mixture of Forms Ib and Vl.
  • This meta-stable form can be prepared by dehydrating Form Ib under vacuum at temperatures of about 45 0 C or greater. Partial hydration of Form Vl will also result in the meta-stable Form lbm-2.
  • Form lbm-2 will convert to Form Ib upon complete hydration under ambient humidity.
  • Form lbm-2 is characterized by an X-ray powder diffraction pattern with peaks as shown in Figure 16.
  • This diffraction pattern matches the pattern that results from addition of the diffraction patterns of Form Ib and Form Vl.
  • the DSC thermogram for Form lbm-2 indicates an onset of dehydration endotherm at about 73 0 C and an onset of crystal melting endotherm at about 177°C, at a scan rate of 10°C/minute.

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Abstract

La présente invention concerne des procédés de préparation de composés de formule (I) ou leurs sels et solvates pharmaceutiquement acceptables. Les composés de la formule (I) sont utiles en tant qu'agents anti-angiogénèse et agents de modulation et/ou inhibition de l'activité de protéines kinases, procurant ainsi des traitements contre le cancer ou contre d'autres maladies associées à la prolifération cellulaire médiée par les protéines kinases.
EP05797459A 2004-11-02 2005-10-21 Procedes de preparation de composes indazole Withdrawn EP1814859A2 (fr)

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US62471904P 2004-11-02 2004-11-02
US62480104P 2004-12-14 2004-12-14
PCT/IB2005/003348 WO2006048761A2 (fr) 2004-11-02 2005-10-21 Procedes de preparation de composes indazole

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AU (1) AU2005300241A1 (fr)
CA (1) CA2591313A1 (fr)
IL (1) IL183605A0 (fr)
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RU (1) RU2007120635A (fr)
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DE2136284A1 (en) * 1971-02-08 1972-08-31 Diamond Shamrock Corp., Cleveland, Ohio (V.StA.) Herbicidal pyrrolidinyl-carboxanilides - from arylisocyanates and pyrrolidines in organic solvents
PE20010306A1 (es) * 1999-07-02 2001-03-29 Agouron Pharma Compuestos de indazol y composiciones farmaceuticas que los contienen utiles para la inhibicion de proteina kinasa

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TW200630345A (en) 2006-09-01
RU2007120635A (ru) 2008-12-10
MX2007006554A (es) 2007-06-19
WO2006048761A3 (fr) 2006-06-22
CA2591313A1 (fr) 2006-05-11
WO2006048761A2 (fr) 2006-05-11

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